New reaction mode of the Horner-Wadsworth-Emmons reaction using Sn(OSO2CF3)2 and N-ethylpiperidine

Article abstract of DOI:10.1039/a608495h

Excellent Z or E selectivity is observed in the Horner-Wadsworth-Emmons reactions of methyl bis(trifluoroethyl)phosphonoacetate 2 with aryl alkyl ketones 3a-d or aldehydes 3f,g using Sn(OSO₂CF₃)₂ in the presence of N-ethylpiperidine, which should have a different reaction mode to those using sodium hydride.

Full text of DOI:10.1039/a608495h

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New reaction mode of the Horner–Wadsworth–Emmons reaction using
Sn(OSO CF ) and N-ethylpiperidine
2
3 2
Shigeki Sano, Kenji Yokoyama, Mari Fukushima, Tetsuo Yagi and Yoshimitsu Nagao*
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770, Japan
Excellent Z or E selectivity is observed in the Horner–
Wadsworth–Emmons reactions of methyl bis(trifluoro-
ethyl)phosphonoacetate 2 with aryl alkyl ketones 3a–d or
a,b-unsaturated esters 4a–d with modest E selectivity (Table 1,
entries 1–4). On the other hand, treatment of 3b–d and 1 with
Sn(OSO CF in the presence of N-ethylpiperidine in THF at
0 °C afforded Z-alkenes 4b–d, respectively, in a highly selective
fashion (Table 2, entries 2–4). Under both sets of reaction
conditions described above, the HWE reactions of aldehydes
2
3 2
)
aldehydes 3f,g using Sn(OSO
2
CF
3
)
2
in the presence of
N-ethylpiperidine, which should have a different reaction
mode to those using sodium hydride.
3
f,g with 1 gave 4f,g in the usual highly E-selective manner
The Horner–Wadsworth–Emmons (HWE) reaction is one of the
(Table 1, entries 6 and 7; Table 2, entries 6 and 7). Poor
stereoselectivity was observed in both reaction systems for
ketone 3e (Table 1, entry 5; Table 2, entry 5). A significant
most efficient methods for the preparation of a,b-unsaturated
1
esters. The reactions of aldehydes with phosphonates bearing
a-substituents that stabilise the carbanion preferentially furnish
the corresponding E-alkenes. Various bases such as sodium
hydride, butyllithium and sodium ethoxide have been employed
in order to generate the phosphonate carbanions. In similar
HWE reactions, mild olefination procedures using lithium and
Table 1 NaH/THF mediated Horner–Wadsworth–Emmons reactions of 1
and 2 with ketones 3a–e and aldehydes 3f,g
a
Phosphono- Ketone or
Yield
(%)
Alkene
(E/Z)
b
c
2
Entry
acetate
aldehyde
t/h
magnesium salts in the presence of tertiary amines or with
3
lithium hydroxide are also available. Interestingly, the reac-
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1
1
1
1
1
1
1
2
2
2
2
2
2
2
3a
3b
3c
3d
3e
3f
66
72
72
72
72
1
100
100
86
88
93
100
79
100
93
82
91
4a (85:15)
4b (62:38)
4c (57:43)
4d (51:49)
4e (53:47)
4f (100:0)
4g (97:3)
5a (45:55)
5b (39:61)
5c (36:64)
5d (35:65)
5e (38:62)d
5f (15:85)
5g (8:92)
4
tions of methyl bis(trifluoroethyl)phosphonoacetate 2 or ethyl
diphenylphosphonoacetate5 with aldehydes selectively yield
Z-alkenes. However, the stereoselectivity of their HWE reac-
tions with ketones has never been investigated in detail because
of their low reactivity and low stereoselectivity.6
d
Herein we describe the stereochemical outcome in the HWE
reactions of ethyl diethylphosphonoacetate 1 and methyl
bis(trifluoroethyl)phosphonoacetate 2 with some aryl alkyl
ketones 3a–e and aldehydes 3f,g using Sn(OSO CF ) in the
2 3 2
presence of N-ethylpiperidine, as shown in Scheme 1.† The
results are shown in Tables 1–3.‡
The conventional HWE reactions of aryl alkyl ketones 3a–d
with phosphonate 1 in the presence of sodium hydride in THF
at 0 °C and then at room temperature gave the corresponding
3g
3a
3b
3c
3d
3e
1
23
23
24
24
23
3
1
1
1
1
1
52
100
94
e
3f
e
3g
3
a
b
Conditions: THF, 0 °C to room temp., 1 or 2/NaH/3 (1.7:1.5:1).
Isolated
) analysis. d HPLC analysis (TSK-GEL
Silica 60, hexane–propan-2-ol. 278 °C.
c 1
yields. H NMR (400 MHz, CDCl
3
e
Sn(OSO2CF3)2,
••
Table
Wadsworth–Emmons reactions of 1 and 2 with ketones 3a–e and aldehydes
3f,g
2
2 3 2
Sn(OSO CF ) /N-ethylpiperidine/THF mediated Horner–
Et
N
Sn
O
P
O
OSO2CF3
OR1
2
R O
O
P
O
2
a
R O
2
OR1
THF or CH2Cl2
R O
2
R O
R1 = R2 = Et
R1 = Me, R2 = CH2CF3
Phosphono- Ketone or
Yield
(%)
Alkene
(E/Z)
1
2
H
b
c
Entry
acetate
aldehyde
t/h
O
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
2
2
2
2
2
2
3a
3b
3c
3d
3e
3f
21
72
19
80
19
20
18
18
17
16
17
17
20
20
—d
44
38
36
4
47
31
95
100
92
95
65
62
44
—
R3
R4
4b (7:93)
4c (6:94)
4d (6:94)
4e (58:42)
4f (100:0)
4g (100:0)
5a (16:84)
5b (16:84)
5c (13:87)
5d (12:88)
5e (36:64)
5f (89:11)
5g (95:5)
3
a–g
R3
R3
CO2R1
H
e
+
R4
CO2R1
R4
H
3g
3a
3b
3c
3d
3e
E-4a–g (R1 = Et)
E-5a–g (R1 = Me)
Z-4a–g (R1 = Et)
Z-5a–g (R1 = Me)
a R3 = Ph, R4 = Me
b R3 = Ph, R4 = Et
c R3 = 2-naphthyl, R4 = Et
d R3 = Ph, R4 = C5H11
e R3 = CH2CH2Ph, R4 = Et
10
11
12
13
14
e
f
3f
f
3g
R3 = Ph, R4 = H
a
f
2 3 2
Conditions: THF, 0 °C, 1 or 2/Sn(OSO CF ) /N-ethylpiperidine/3
g R3 = CH2CH2Ph, R4 = H
(1.4:1.68:1.54:1).
analysis. d Aldol product (78% yield). HPLC analysis (TSK-GEL Silica
60, hexane–propan-2-ol. 278 °C.
b
Isolated yields.
c
1
H NMR (400 MHz, CDCl3)
e
f
Scheme 1
Chem. Commun., 1997
559

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Fig. 1
Table
3
Sn(OSO
2
CF
3
)
2
/N-ethylpiperidine/CH
2
Cl
2
mediated Horner–
reactions of 3f,g in THF also always gave the corresponding
Z-alkenes 5f [E:Z = 28:72 (0 °C) and 15:85 (278 °C)] and 5g
Wadsworth–Emmons reactions of 2 with ketones 3a–e and aldehydes
a
3f,g
[
E:Z = 18:82 (0 °C) and 8:92 (278 °C)], respectively.
On the basis of the experimental results described above, the
Ketone or
aldehyde
Yield
Alkene
(E/Z)c
2 3 2
high Z-selectivity in the Sn(OSO CF ) -mediated HWE reac-
b
Entry
t/h
(%)
tions of ketones 3a–d with 1 and 2 can be rationalised in terms
II
of six-membered transition state A (e.g. 3b) involving Sn
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
15
18
18
18
15
23
24
84
90
95
98
59
29
5a (2:98)
5b ( < 1: > 99)
5c (2:98)
5d (1:99)
5e (40:60)
chelation (Fig. 1). Another possible transition state B favouring
E-selectivity will be disadvantageous due to 1,3-diaxial steric
1
repulsion between the ethyl (or other alkyl) group and the R O
d
group. This speculative consideration is supported by the fact
that 1-methyl-1-phenylcyclohexane exhibits an axial preference
for the phenyl group in spite of the relatively large A value of the
e
3f
5f (94:6)
—
e
f
3g
—
2
1
phenyl group (2.87 kcal mol ) compared with the ethyl group
a
Conditions: CH
2
b
Cl
2
,
0
°C, 2/Sn(OSO
2
CF
H NMR (400 MHz, CDCl
HPLC analysis (TSK-GEL Silica 60, hexane–propan-2-ol.
3 2
) /N-ethylpiperidine/3
2
1 7
c
1
(1.8 kcal mol ). The E-selectivity in the Sn(OSO
mediated HWE reactions of aldehydes 3f,g with 1 in THF at
Cl at
2 3 2
CF ) -
(1.4:1.68:1.54:1). Isolated yields.
3
)
d
analysis.
e
f
0 °C, with 2 in THF at 265 to 278 °C and with 2 in CH
2
78 °C. No reaction.
2
2
room temperature to 278 °C may also be explained in terms of
II
improvement in the selectivity and yield was found when Still’s
six-membered transition state C (e.g. 3f). The Sn -promoted
reagent, methyl bis(trifluoroethyl)phosphonoacetate 2, was
HWE reactions of the reactive reagent 2 with aldehydes 3f,g in
THF at higher reaction temperatures than 265 °C seem to
proceed in a non-chelation-controlled manner like the case of
NaH.
II
used under the Sn -promoted (Tables 2 and 3). In particular, the
reactions of 3a–d with 2 employing Sn(OSO CF and
N-ethylpiperidine in CH Cl at 0 °C afforded the corresponding
2
3 2
)
2
2
Z-alkenes 5a–d in a more highly selective manner (Table 3,
entries 1–4) than those carried out in THF (Table 2, entries
Footnotes
8–11). The reactions using the NaH procedure resulted in low
†
Presented in part at the 114th Annual Meeting of the Pharmaceutical
Z-selectivity (Table 1, entries 8–11). The HWE reactions of
aldehydes 3f,g with 2 in the presence of NaH in THF at 278 °C
gave Z-5f,g with similar good selectivity to that using Still’s
reagent (Table 1, entries 13 and 14). The same reactions
Society of Japan, Tokyo, March 29–31, 1994; abstract paper 2, p. 79.
‡ Full characterisation will be published as part of a forthcoming paper.
References
employing Sn(OSO
CH Cl at 278 °C, on the contrary, gave E-5f,g with fairly good
selectivity, as we anticOipaRted (Table 2, entries 13 and 14; Table
2 3 2
CF ) and N-ethylpiperidine in THF or
1
B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863 and
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2
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1
2
M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune,
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II
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H
;
SO
2
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3
)
2
/N-ethylpiperidine/3f or 3g (1.4:1.68:1.54:1)] was
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H
••
H
••
H
variable depending on the reaction temperatures as follows;
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Sn
O
Sn
O
S
4
1
6
9:81 (230 °C, 72%), 12:88 (245 °C, 68%), 26:74 (256 °C,
Et
5 K. Ando, Tetrahedron Lett., 1995, 36, 4105.
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O
O
OSO CF
OSO CF
6 S. K. Thompson and C. H. He 2a thcoc 3k , J. Org. Chem., 1990, 55, 3386.
2
3
ratio (temperaPture, yield) of 5g = 6:94 (0 °C, 85%), < 1: > 99
P
P
O
7 N. L. Allinger and L. A. Freiberg, J. Org. Chem., 1966, 31, 894;
O
(
240 °C 2, 53%) and 95:5 (278 °C, 44%). However, the similar
2
2
N. L. Allinger and M. T. Tribble, Tetrahedron Lett., 1971, 3259;
R O
R O
R O
Sn -promoted reactio n2 of 3f in CH
II
2
Cl
always afforded the
2
2
E. L. Eliel and M. Manoharan, J. Org. Chem., 1981, 46, 1959.
OR
OR
O
E-alkene 5f (E:Z = 78:22 to 94:6) irrespective of the reaction
temperature (room temperature to 278 °C). The NaH-promoted
Received, 19th December 1996; Com. 6/08495H
1
2
1
2
1
2
A
R = R = Et
B
R = R = Et
or
C
R = R =
or
R = Me,
or
1
2
1
2
1
R = Me, R = CH CF
R = Me, R = CH CF
3
2
3
2
Z-alkene
E-alkene
E-alkene
8
495H/2
5
60
Chem. Commun., 1997